PRKCSH

Summary

PRKCSH (PRKCSH beta subunit of glucosidase II, HGNC:9411) is a protein-coding gene on chromosome 19p13.2, encoding Glucosidase 2 subunit beta (P14314). Regulatory subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. The encoded protein is an acidic phosphoprotein known to be a substrate for protein kinase C. Mutations in this gene have been associated with the autosomal dominant polycystic liver disease. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5589 — RefSeq curated summary.

At a glance

• Gene–disease (curated): polycystic liver disease 1 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 20
• Clinical variants (ClinVar): 907 total — 38 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001289104

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9411
Approved symbol	PRKCSH
Name	PRKCSH beta subunit of glucosidase II
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	VASAP-60, GIIB, PKCSH, 80K-H, AGE-R2, GIIbeta, GluIIbeta
Ensembl gene	ENSG00000130175
Ensembl biotype	protein_coding
OMIM	177060
Entrez	5589

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 37 protein_coding, 7 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000585325, ENST00000585540, ENST00000586486, ENST00000587290, ENST00000587327, ENST00000587509, ENST00000588269, ENST00000589126, ENST00000589838, ENST00000589990, ENST00000590098, ENST00000591462, ENST00000591510, ENST00000591946, ENST00000592435, ENST00000592445, ENST00000592741, ENST00000593053, ENST00000593101, ENST00000593104, ENST00000676823, ENST00000677123, ENST00000852989, ENST00000852990, ENST00000852991, ENST00000852992, ENST00000852993, ENST00000852994, ENST00000852995, ENST00000852996, ENST00000852997, ENST00000852998, ENST00000852999, ENST00000853000, ENST00000853001, ENST00000853002, ENST00000853003, ENST00000853004, ENST00000853005, ENST00000853006, ENST00000853007, ENST00000853008, ENST00000853009, ENST00000916401, ENST00000951514, ENST00000951515, ENST00000951516, ENST00000951517

RefSeq mRNA: 7 — MANE Select: NM_001289104 NM_001001329, NM_001289102, NM_001289103, NM_001289104, NM_001379608, NM_001379609, NM_002743

CCDS: CCDS32911, CCDS45977, CCDS74286

Canonical transcript exons

ENST00000677123 — 18 exons

Exon	Start	End
ENSE00000679902	11446272	11446350
ENSE00000679903	11445389	11445473
ENSE00000679905	11442386	11442515
ENSE00000679908	11441240	11441357
ENSE00000864733	11450646	11450968
ENSE00000864738	11448222	11448291
ENSE00001297744	11449266	11449428
ENSE00003473664	11447439	11447618
ENSE00003544580	11448914	11448988
ENSE00003550413	11449076	11449175
ENSE00003557728	11437876	11437971
ENSE00003585667	11438067	11438124
ENSE00003607499	11436389	11436505
ENSE00003624440	11436041	11436196
ENSE00003638344	11447693	11447789
ENSE00003663638	11447074	11447160
ENSE00003678825	11448540	11448629
ENSE00003909863	11435635	11435706

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.6451 / max 217.0966, expressed in 1667 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173920	240.2410	1827
45608	13.6451	1667
173926	4.0159	428
173927	1.3303	831
173922	1.3169	844
173921	1.1611	653
173923	0.7458	441
173928	0.5445	255
45610	0.3678	111
173918	0.2860	119

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.33	gold quality
type B pancreatic cell	CL:0000169	99.18	gold quality
olfactory bulb	UBERON:0002264	99.15	silver quality
left ovary	UBERON:0002119	98.92	gold quality
right ovary	UBERON:0002118	98.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.81	gold quality
granulocyte	CL:0000094	98.75	gold quality
right uterine tube	UBERON:0001302	98.66	gold quality
body of pancreas	UBERON:0001150	98.59	gold quality
body of uterus	UBERON:0009853	98.58	gold quality
endocervix	UBERON:0000458	98.57	gold quality
right lobe of thyroid gland	UBERON:0001119	98.55	gold quality
adenohypophysis	UBERON:0002196	98.51	gold quality
left lobe of thyroid gland	UBERON:0001120	98.47	gold quality
gall bladder	UBERON:0002110	98.38	gold quality
spinal cord	UBERON:0002240	98.38	gold quality
ectocervix	UBERON:0012249	98.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.37	gold quality
body of stomach	UBERON:0001161	98.34	gold quality
minor salivary gland	UBERON:0001830	98.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.33	gold quality
transverse colon	UBERON:0001157	98.31	gold quality
mucosa of transverse colon	UBERON:0004991	98.31	gold quality
thyroid gland	UBERON:0002046	98.30	gold quality
pituitary gland	UBERON:0000007	98.27	gold quality
skin of abdomen	UBERON:0001416	98.24	gold quality
skin of leg	UBERON:0001511	98.24	gold quality
cortical plate	UBERON:0005343	98.18	gold quality
ganglionic eminence	UBERON:0004023	98.16	gold quality
cerebellar hemisphere	UBERON:0002245	98.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	129.35
E-ANND-3	yes	13.55
E-CURD-112	no	2.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

26 targeting PRKCSH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-5591-3P	96.23	67.03	489
HSA-MIR-2861	95.24	65.47	1056

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• Mutations in this protein cause isolated autosomal dominant polycystic liver disease. (PMID:12529853)
• germline mutations in PRKCSH as the probable cause of autosomal dominant polycystic liver disease (PMID:12577059)
• autosomal dominant polycystic liver disease is genetically heterogeneous (PMID:15057895)
• role of hepatocystin in carbohydrate processing and quality control of newly synthesized glycoproteins in the endoplasmic reticulum (PMID:15188177)
• results identify 80K-H as a new player involved in GLUT4 vesicle transport and identify a link between a kinase involved in the insulin signalling cascade, PKCzeta, and a known component of the GLUT4 vesicle trafficking pathway, munc18c (PMID:15707389)
• the majority of cysts from PRKCSH mutation carriers did not express hepatocystin (PMID:18224332)
• Hepatocystin is not secreted in liver cyst fluids of autosomal dominant polycystic liver disease patients, suggesting that mutant hepatocystin is either not produced or degraded intracellularly. (PMID:18419150)
• 80K-H is a novel regulator of IP3R1 activity, and it may contribute to neuronal functions. (PMID:18990696)
• These results indicate that insulin induces dynamic associations between PKCzeta, 80K-H, and munc18c and that 80K-H may act as a key signaling link between PKCzeta and munc18c in live cells. (PMID:19061073)
• Our results suggest that PRKCSH gene is not a major genetic cause of PCLD and there may be at least another locus responsible for the disease in Taiwan. (PMID:19308730)
• PRKCSH functions as a chaperone-like molecule, which prevents endoplasmic reticulum-associated degradation of TRPP2. (PMID:19801576)
• identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non-sense mutations, and eight missense mutations (PMID:20095989)
• The common SNPs tested in DDOST, PRKCSH and LGALS3 do not seem to be associated with diabetic micro- or macrovascular complications or with type 1 diabetes in Finnish patients. (PMID:20490454)
• Results provide evidence that mutations at the coding PRKCSH GAG repeat are a target of MSI and are selectively associated with the MSI-H phenotype in gastric carcinomas. (PMID:21371016)
• The induction of autophagy by hepatocystin deficiency is mediated through mammalian target of rapamycin (mTOR). (PMID:21681021)
• Polycystic liver disease is recessive at the cellular level, and loss of functional PRKCSH is an important step in cystogenesis. (PMID:21856269)
• This study demonstrated that Large copy number variations on germline level are not present in patients with a clinical diagnosis of Severe Polycystic Liver Disease. (PMID:26365003)
• Results suggest that loss of PRKCSH and SEC63 leads to general defects in ciliogenesis, while quenching of the Wnt signaling cascade is cholangiocyte-restricted. (PMID:28973524)
• Potential role of PRKCSH in lung cancer: bioinformatics analysis and a case study of Nano ZnO. (PMID:35254362)
• PRKCSH serves as a potential immunological and prognostic biomarker in pan-cancer. (PMID:38245572)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkcsh	ENSDARG00000004470
mus_musculus	Prkcsh	ENSMUSG00000003402
rattus_norvegicus	Prkcsh	ENSRNOG00000013360
drosophila_melanogaster	CG7685	FBGN0038619
caenorhabditis_elegans		WBGENE00014249

Paralogs (1): GNPTG (ENSG00000090581)

Protein

Protein identifiers

Glucosidase 2 subunit beta — P14314 (reviewed: P14314)

Alternative names: 80K-H protein, Glucosidase II subunit beta, Protein kinase C substrate 60.1 kDa protein heavy chain

All UniProt accessions (9): P14314, A0A0C4DGP4, A0A7I2V2T6, K7EIP3, K7EJ70, K7EKX1, K7EL27, K7ELL7, K7EPW7

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of glucosidase II that cleaves sequentially the 2 innermost alpha-1,3-linked glucose residues from the Glc(2)Man(9)GlcNAc(2) oligosaccharide precursor of immature glycoproteins. Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia.

Subunit / interactions. Heterodimer of a catalytic alpha subunit (GANAB) and a beta subunit (PRKCSH). Binds glycosylated PTPRC.

Subcellular location. Endoplasmic reticulum.

Disease relevance. Polycystic liver disease 1 with or without kidney cysts (PCLD1) [MIM:174050] An autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. A subset of patients may develop kidney cysts that usually do not result in clinically significant renal disease. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycan metabolism; N-glycan metabolism.

Isoforms (2)

UniProt ID	Names	Canonical?
P14314-1	1	yes
P14314-2	2

RefSeq proteins (7): NP_001001329, NP_001276031, NP_001276032, NP_001276033, NP_001366537, NP_001366538, NP_002734 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR009011	Man6P_isomerase_rcpt-bd_dom_sf	Homologous_superfamily
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028146	PRKCSH_N	Domain
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036607	PRKCSH	Domain
IPR039794	Gtb1-like	Family
IPR044865	MRH_dom	Domain

Pfam: PF12999, PF13015, PF13202

Enzyme classification (BRENDA):

• EC 3.2.1.207 — mannosyl-oligosaccharide alpha-1,3-glucosidase (BRENDA: 26 organisms, 73 substrates, 66 inhibitors, 27 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MALTOSE	0.43–57.7	4
P-NITROPHENYL ALPHA-D-GLUCOPYRANOSIDE	0.78–481	4
4-NITROPHENYL ALPHA-D-GLUCOPYRANOSIDE	2.2–2.82	3
P-NITROPHENYL-ALPHA-D-GLUCOPYRANOSIDE	0.5–0.92	3
4-METHYLUMBELLIFERYL ALPHA-D-GLUCOPYRANOSIDE	0.013–0.019	2
4-METHYLUMBELLIFERYL-ALPHA-D-GLUCOPYRANOSIDE	0.0003	1
4-METHYLUMBELLIFERYL-ALPHA-D-GLUCOSIDE	0.0552	1
4-METHYLUMBELLYFERYL ALPHA-D-GLUCOPYRANOSIDE	0.055	1
MALTOHEXAOSE	15.3	1
MALTOTRIOSE	26.7	1
N-[[2-CARBOXY-5-(4-METHOXYPHENYL)THIOPHEN-3-YL]C	0.49	1
NIGEROSE	2.13	1
P-NITROPHENYL-2-DEOXY-ALPHA-D-GLUCOPYRANOSIDE	0.76	1
SUCROSE	15.3	1

UniProt features (73 total): binding site 19, strand 11, disulfide bond 8, sequence variant 8, modified residue 7, domain 5, compositionally biased region 3, helix 3, glycosylation site 2, region of interest 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8D43	ELECTRON MICROSCOPY	2.88
8EMR	ELECTRON MICROSCOPY	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14314-F1	84.33	0.66

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (19): 49; 50; 53; 53; 55; 57; 63; 64; 91; 94; 96; 98 …

Post-translational modifications (7): 24, 89, 166, 168, 383, 390, 434

Disulfide bonds (8): 39–58, 56–70, 77–99, 97–112, 100–116, 415–428, 471–500, 485–512

Glycosylation sites (2): 72, 476

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-879415	Advanced glycosylation endproduct receptor signaling
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-901042	Calnexin/calreticulin cycle
R-HSA-9683686	Maturation of spike protein
R-HSA-9694548	Maturation of spike protein
R-HSA-9768727	Regulation of CDH1 posttranslational processing and trafficking to plasma membrane

MSigDB gene sets: 640 (showing top): GOBP_N_GLYCAN_PROCESSING, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, LUCAS_HNF4A_TARGETS_UP, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (6): liver development (GO:0001889), N-glycan processing (GO:0006491), intracellular signal transduction (GO:0035556), in utero embryonic development (GO:0001701), negative regulation of neuron projection development (GO:0010977), nitrogen cycle metabolic process (GO:0071941)

GO Molecular Function (8): protein kinase C binding (GO:0005080), calcium ion binding (GO:0005509), transmembrane transporter binding (GO:0044325), phosphoprotein binding (GO:0051219), RNA binding (GO:0003723), protein binding (GO:0005515), protein-containing complex binding (GO:0044877), metal ion binding (GO:0046872)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), glucosidase II complex (GO:0017177), intracellular membrane-bounded organelle (GO:0043231)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Metabolism of proteins	1
Asparagine N-linked glycosylation	1
Innate Immune System	1
Post-translational protein modification	1
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1
Translation of Structural Proteins	1
Regulation of CDH1 Expression and Function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
protein binding	2
binding	2
gland development	1
hepaticobiliary system development	1
protein N-linked glycosylation	1
glycoprotein biosynthetic process	1
signal transduction	1
chordate embryonic development	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
metabolic process	1
protein kinase binding	1
metal ion binding	1
nucleic acid binding	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
endoplasmic reticulum protein-containing complex	1
glucosidase complex	1
membrane-bounded organelle	1
intracellular organelle	1

Protein interactions and networks

STRING

1444 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKCSH	SEC63	Q9UGP8	978
PRKCSH	GANAB	Q14697	934
PRKCSH	DDOST	P39656	932
PRKCSH	PKD2	Q13563	893
PRKCSH	HERPUD1	Q15011	769
PRKCSH	MARCKS	P29966	764
PRKCSH	PKD1	P98161	761
PRKCSH	ALG8	Q9BVK2	719
PRKCSH	PKHD1	P08F94	669
PRKCSH	CANX	P27824	652
PRKCSH	SEC61B	P38390	647
PRKCSH	SCARB1	Q8WTV0	637
PRKCSH	MSR1	P21757	632
PRKCSH	LGALS3	P17931	609
PRKCSH	PRKD1	Q15139	603

IntAct

119 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
GANAB	PRKCSH	psi-mi:“MI:0407”(direct interaction)	0.610
GANAB	PRKCSH	psi-mi:“MI:0915”(physical association)	0.610
PRKCSH	GANAB	psi-mi:“MI:0194”(cleavage reaction)	0.610
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
GANAB	PRKCSH	psi-mi:“MI:0407”(direct interaction)	0.560
PRKCSH	GANAB	psi-mi:“MI:0194”(cleavage reaction)	0.560
RGS2	PRKCSH	psi-mi:“MI:0915”(physical association)	0.550
PRKCSH	AURKA	psi-mi:“MI:0914”(association)	0.530
POP4	NME2P1	psi-mi:“MI:0914”(association)	0.530
HCFC2	SETD1A	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
env	PSMD11	psi-mi:“MI:0914”(association)	0.460
env	APP	psi-mi:“MI:0914”(association)	0.460
env	PGRMC1	psi-mi:“MI:0914”(association)	0.460
	PRKCSH	psi-mi:“MI:0194”(cleavage reaction)	0.440
DMD	PRKCSH	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (359): PRKCSH (Affinity Capture-MS), PRKCSH (Reconstituted Complex), PRKCSH (Affinity Capture-MS), DNA2 (Affinity Capture-MS), ANAPC7 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), TSC2 (Affinity Capture-MS), PEX14 (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), BBS1 (Affinity Capture-MS), AURKA (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), COPG1 (Affinity Capture-MS), INTS7 (Affinity Capture-MS)

ESM2 similar proteins: A2WNF5, I1HNB2, O08795, O23144, O73683, O93279, P05067, P08592, P0CT24, P12023, P14314, P14599, P15943, P53601, P79307, Q06335, Q06481, Q10651, Q12797, Q16891, Q28034, Q28056, Q498F0, Q4IEA7, Q4WCG2, Q5BDB9, Q5IS80, Q5JSH3, Q5NBP9, Q5TUF1, Q5XIN3, Q5ZM60, Q60495, Q6QD51, Q76M96, Q7KRW8, Q872S3, Q8AXP2, Q8BSY0, Q8CAQ8

Diamond homologs: O08795, P14314, Q04924, Q28034, A2WNF5, Q5NBP9, Q9FM96, Q9USH8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

907 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	30
Uncertain significance	399
Likely benign	204
Benign	103

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048653	NM_001289104.2(PRKCSH):c.374_375del (p.Glu125fs)	Pathogenic
1071285	NM_002662.5(PLD1):c.880A>T (p.Lys294Ter)	Pathogenic
1255531	NM_001289104.2(PRKCSH):c.1290C>A (p.Tyr430Ter)	Pathogenic
1255627	NM_001289104.2(PRKCSH):c.430_432delinsAATAAGG (p.Leu144fs)	Pathogenic
1255667	NM_001289104.2(PRKCSH):c.487C>T (p.Gln163Ter)	Pathogenic
1313339	NM_002662.5(PLD1):c.607-2A>C	Pathogenic
13238	NM_001289104.2(PRKCSH):c.1362-2A>G	Pathogenic
13239	NM_001289104.2(PRKCSH):c.292+1G>C	Pathogenic
13240	NM_001289104.2(PRKCSH):c.1461+2_1461+3del	Pathogenic
13241	NM_001289104.2(PRKCSH):c.1261C>T (p.Gln421Ter)	Pathogenic
13243	NM_001289104.2(PRKCSH):c.215dup (p.Asn72fs)	Pathogenic
1435046	NM_001289104.2(PRKCSH):c.353dup (p.Lys119fs)	Pathogenic
194734	NM_001289104.2(PRKCSH):c.1481_1484del (p.Lys494fs)	Pathogenic
1994589	NM_001289104.2(PRKCSH):c.372_375del (p.Arg124fs)	Pathogenic
2042304	NM_002662.5(PLD1):c.1276_1279del (p.Ala426fs)	Pathogenic
2074815	NM_002662.5(PLD1):c.2416del (p.Ile805_Leu806insTer)	Pathogenic
2424512	NC_000003.11:g.(?171376983)(171410252_?)del	Pathogenic
2752177	NM_001289104.2(PRKCSH):c.1467_1477del (p.Leu490fs)	Pathogenic
2754965	NM_001289104.2(PRKCSH):c.481G>T (p.Glu161Ter)	Pathogenic
2903572	NM_002662.5(PLD1):c.2178del (p.Ala727fs)	Pathogenic
3239271	NM_002662.5(PLD1):c.472C>T (p.Arg158Ter)	Pathogenic
3251798	NM_002662.5(PLD1):c.2034del (p.Trp678fs)	Pathogenic
3340689	NM_001289104.2(PRKCSH):c.1461+1G>A	Pathogenic
3583455	NM_001289104.2(PRKCSH):c.1289dup (p.Tyr430Ter)	Pathogenic
4056489	NM_002662.5(PLD1):c.892C>T (p.Arg298Ter)	Pathogenic
426089	NM_002662.5(PLD1):c.1325A>C (p.His442Pro)	Pathogenic
426091	NM_002662.5(PLD1):c.2882+2T>C	Pathogenic
4531704	NM_001289104.2(PRKCSH):c.668del (p.Asp223fs)	Pathogenic
4534653	NM_001289104.2(PRKCSH):c.135del (p.Ile46fs)	Pathogenic
4716717	NM_001289104.2(PRKCSH):c.985G>T (p.Glu329Ter)	Pathogenic

SpliceAI

4426 predictions. Top by Δscore:

Variant	Effect	Δscore
19:11422624:CTGG:C	acceptor_gain	1.0000
19:11422625:TGG:T	acceptor_gain	1.0000
19:11422628:C:CC	acceptor_gain	1.0000
19:11422857:AACGA:A	acceptor_gain	1.0000
19:11422858:ACGA:A	acceptor_gain	1.0000
19:11422859:CGA:C	acceptor_gain	1.0000
19:11422859:CGAC:C	acceptor_gain	1.0000
19:11422862:C:CC	acceptor_gain	1.0000
19:11422862:CT:C	acceptor_loss	1.0000
19:11423873:T:TA	donor_loss	1.0000
19:11423875:A:AC	donor_gain	1.0000
19:11423875:A:AT	donor_loss	1.0000
19:11423876:C:CA	donor_gain	1.0000
19:11423876:CG:C	donor_gain	1.0000
19:11423876:CGTG:C	donor_gain	1.0000
19:11424035:C:CT	acceptor_gain	1.0000
19:11424136:C:CC	acceptor_gain	1.0000
19:11426139:CCCA:C	donor_loss	1.0000
19:11426140:CCAC:C	donor_loss	1.0000
19:11426142:A:AG	donor_loss	1.0000
19:11426143:CCTT:C	donor_loss	1.0000
19:11426578:C:CT	acceptor_gain	1.0000
19:11426582:G:C	acceptor_gain	1.0000
19:11426582:G:GC	acceptor_gain	1.0000
19:11426678:CCTA:C	donor_loss	1.0000
19:11426691:AGG:A	donor_gain	1.0000
19:11426781:TGGT:T	acceptor_gain	1.0000
19:11426782:GGT:G	acceptor_gain	1.0000
19:11426782:GGTCT:G	acceptor_loss	1.0000
19:11426783:GTCTG:G	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000359954 (19:11441318 C>A), RS1000374862 (19:11441010 A>G), RS1000428542 (19:11447176 G>A), RS1001140718 (19:11434346 C>T), RS1001201594 (19:11435854 G>A), RS1001257845 (19:11440589 C>T), RS1001513388 (19:11450050 T>A), RS1001564064 (19:11449831 G>A,C), RS1001606088 (19:11449504 A>G), RS1001687660 (19:11440387 T>G), RS1001689984 (19:11446195 G>A), RS1001701048 (19:11439346 A>G), RS1001753518 (19:11445939 G>A,C,T), RS1001798863 (19:11445046 C>T), RS1001869203 (19:11443513 T>G)

Disease associations

OMIM: gene MIM:177060 | disease phenotypes: MIM:212093, MIM:174050

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiac valvular defect, developmental	Definitive	Autosomal recessive
polycystic liver disease 1	Definitive	Autosomal dominant
PLD1-related congenital heart disease	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
polycystic liver disease 1	Definitive	AD
PLD1-related congenital heart disease	Definitive	AR

Mondo (5): cardiac valvular defect, developmental (MONDO:0008913), autosomal dominant polycystic liver disease (MONDO:0000447), polycystic liver disease 1 (MONDO:0008265), biliary tract disorder (MONDO:0004868), PLD1-related congenital heart disease (MONDO:1010144)

Orphanet (1): Isolated polycystic liver disease (Orphanet:2924)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000072	Hydroureter
HP:0000107	Renal cyst
HP:0000126	Hydronephrosis
HP:0000952	Jaundice
HP:0000961	Cyanosis
HP:0000969	Edema
HP:0001541	Ascites
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001634	Mitral valve prolapse
HP:0001642	Pulmonic stenosis
HP:0001653	Mitral regurgitation
HP:0001654	Abnormal heart valve morphology
HP:0001655	Patent foramen ovale
HP:0001704	Tricuspid valve prolapse
HP:0001718	Mitral stenosis
HP:0001732	Abnormality of the pancreas
HP:0001789	Hydrops fetalis
HP:0002020	Gastroesophageal reflux
HP:0002027	Abdominal pain
HP:0002086	Abnormality of the respiratory system
HP:0002093	Respiratory insufficiency
HP:0002094	Dyspnea
HP:0002239	Gastrointestinal hemorrhage
HP:0002240	Hepatomegaly
HP:0002617	Vascular dilatation
HP:0003155	Elevated circulating alkaline phosphatase concentration

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST003563_11	Presence of antiphospholipid antibodies	3.000000e-06
GCST003563_12	Presence of antiphospholipid antibodies	4.000000e-06
GCST003563_6	Presence of antiphospholipid antibodies	5.000000e-08
GCST004621_137	Red cell distribution width	7.000000e-43
GCST004621_138	Red cell distribution width	3.000000e-11
GCST004621_139	Red cell distribution width	2.000000e-15
GCST004621_140	Red cell distribution width	2.000000e-09
GCST004621_141	Red cell distribution width	5.000000e-34
GCST006804_1	Red cell distribution width	5.000000e-13
GCST006804_3	Red cell distribution width	9.000000e-15
GCST006804_87	Red cell distribution width	2.000000e-26
GCST007012_1	Cerebrospinal fluid AB1-42 levels	5.000000e-07
GCST009240_396	Serum metabolite levels (CMS)	1.000000e-12
GCST90002381_195	Eosinophil count	7.000000e-10
GCST90002404_61	Red cell distribution width	2.000000e-43
GCST90002404_62	Red cell distribution width	1.000000e-42
GCST90002404_63	Red cell distribution width	8.000000e-39
GCST90002404_64	Red cell distribution width	2.000000e-37
GCST90002404_65	Red cell distribution width	1.000000e-17
GCST90002406_49	Reticulocyte fraction of red cells	7.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004842	eosinophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001660	Biliary Tract Diseases	C06.130
C565882	Cardiac Valvular Defect, Developmental (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5242 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	57.67	nM	CHEMBL5653589
7.24	ED50	57.67	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149082: Binding affinity to human PRKCSH incubated for 45 mins by Kinobead based pull down assay	kd	0.0577	uM

CTD chemical–gene interactions

63 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	3
sodium arsenite	increases expression	3
epigallocatechin gallate	increases expression, affects cotreatment	2
Air Pollutants	affects cotreatment, increases abundance, increases expression	2
Cadmium	increases abundance, increases palmitoylation, decreases expression, decreases reaction	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
sodium arsenate	decreases expression	1
titanium dioxide	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects localization, increases expression, affects cotreatment	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression	1
tetrabromobisphenol A	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
sulindac sulfide	decreases expression	1
ochratoxin A	increases acetylation, increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
cupric oxide	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652124	Binding	Binding affinity to human PRKCSH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3EW	Abcam HEK293T PRKCSH KO	Transformed cell line	Female
CVCL_E2HV	HAP1 PRKCSH (-)	Cancer cell line	Male

Clinical trials (associated diseases)

17 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01157858	PHASE2	COMPLETED	Everolimus and LongActing Octreotide Trial in Polycystic Livers
NCT01670110	PHASE2	COMPLETED	Pasireotide LAR in Severe Polycystic Liver Disease
NCT02021110	PHASE2	COMPLETED	Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease
NCT05478083	PHASE2	RECRUITING	A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease
NCT00426153	PHASE2/PHASE3	COMPLETED	Octreotide in Severe Polycystic Liver Disease
NCT00565097	PHASE2/PHASE3	COMPLETED	Lanreotide as Treatment of Polycystic Livers
NCT00771888	PHASE2/PHASE3	UNKNOWN	Open-Label Extension of LOCKCYST Trial
NCT01315795	PHASE2/PHASE3	COMPLETED	Lanreotide Autogel in the Treatment of Symptomatic Polycystic Liver Disease
NCT05281328	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Assess the Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With PLD
NCT00934791	Not specified	TERMINATED	Polycystic Liver Disease in Kidney Transplant
NCT01354405	Not specified	COMPLETED	Somatostatin Analogues as a Volume Reducing Treatment of Polycystic Livers (RESOLVE)
NCT02173080	Not specified	COMPLETED	Development and Assessment of The Polycystic Liver Disease Questionnaire (PLD-Q).
NCT03960710	Not specified	UNKNOWN	Automatic Segmentation of Polycystic Liver
NCT04645251	Not specified	RECRUITING	Polycystic Liver Disease Registry (UK)
NCT05215964	Not specified	UNKNOWN	The Association Between Skeletal Muscle Mass and Severity of Polycystic Liver Disease and Polycystic Kidney Disease
NCT05500157	Not specified	UNKNOWN	Assessment of Treatment With Laparoscopic Fenestration or Aspiration Sclerotherapy for Large Symptomatic Hepatic Cysts
NCT04111692	Not specified	RECRUITING	A Prospective Observational Study of Foam Sclerotherapy .